Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia

Genes Dev. 2016 Sep 1;30(17):1943-55. doi: 10.1101/gad.283499.116. Epub 2016 Sep 15.


The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. The mechanism involved activation of AKT and noncanonical activation of the GLI family transcription factor GLI2. GLI2 was phosphorylated at Ser230 in an AKT-dependent fashion and directly regulated Tgfa expression in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the growth of Kras(G12D)/Tp53(R172H) pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating Kras(G12D)-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.

Keywords: AKT signaling; EGFR signaling; acinar-to-ductal metaplasia; hedgehog signaling; stromal fibroblast.

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / pathology
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • ErbB Receptors / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / pathology
  • Gene Deletion
  • Kruppel-Like Transcription Factors / metabolism
  • Metaplasia / genetics*
  • Metaplasia / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology*
  • Signal Transduction / genetics
  • Smoothened Receptor / genetics*
  • Smoothened Receptor / metabolism*
  • Transforming Growth Factor alpha / metabolism
  • Tumor Cells, Cultured
  • Zinc Finger Protein Gli2


  • Gli2 protein, mouse
  • Kruppel-Like Transcription Factors
  • Smo protein, mouse
  • Smoothened Receptor
  • Transforming Growth Factor alpha
  • Zinc Finger Protein Gli2
  • EGFR protein, mouse
  • ErbB Receptors